Benzofuran 2-carbox amides useful as inhibitors of leukoriene biosynthesis

ABSTRACT

Compounds of the Formula I: ##STR1## and pharmaceutically acceptable salts thereof are inhibitors of leukotriene biosynthesis. These compounds inhibit the mammalian 5-lipoxygenase enzyme, thus preventing the metabolism of arachidonic acid to the leukotrienes. These compounds are thus useful in the treatment of asthma, allergic disorders, inflammation, skin diseases and certain cardiovascular disorders.

This is a division of Ser. No. 152,215, Feb. 4, 1988, U.S. Pat. No. 4,822,803, which is a division of Ser. No. 1,262, Jan. 7, 1987, U.S. Pat. No. 4,745,127, which is a division of Ser. No. 725,265, Apr. 19, 1985, U.S. Pat. No. 4,663,347, which is a continuation-in-part of Ser. No. 661,645, Oct. 17, 1984, abandoned, which is a continuation-in-part of Ser. No. 547,508, Oct. 31, 1983, abandoned.

U.S. Pat. No. 4,663,347 (Atkinson, et al.) is incorporated herein by reference in its entirety.

One embodiment of the present invention is a pharmaceutical composition containing a compound of the Formula I and an acceptable pharmaceutical carrier: ##STR2## wherein: Z is a bond, CR₁₄ ═CR₁₅ or CHR₁₄ --CHR₁₅ ;

X is O, S, SO, or SO₂ ;

R₂ is H, OH, C₁ to C₂₀ alkoxy, including straight chain or branched chain, cycloalkyl, bicycloalkyl, tricycloalkyl or tetracycloalkyl;

Ar₁ --C₁ to C₃ alkoxy;

NR₈ Ar₁, wherein R₈ and Ar₁ can optionally be joined to form a heterocyclic ring having 5 to 8 atoms;

--NR₈ Het;

--N(R₈)CH₂ Ar₁ ;

--N(R₁₃)--N(R₁₃)₂ wherein each R₁₃ is independently hydrogen, R₈, R₉, Ar₁ or Het;

--NH--CH═C(Ar₁)₂ ;

--O(CH₂)_(n) NR₈ R₉ wherein n is 2 to 4;

--Z--Ar₁ ; ##STR3## lower acyloxy-lower alkoxy ##STR4## --CH₂ OH; --(CH₂)_(n) Ar₁ wherein n is 0 to 3;

--(CH₂)_(n) COOR₆ wherein n is 0 to 6;

C₁ to C₂₀ alkyl; Ar₁ ; Het; (CH₂)_(n) NR₈ R₉

wherein n is 1 to 3; or

Het; ##STR5## and R₁, R₃, R₄, T and V are each independently selected from:

(1) hydrogen;

(2) alkyl having 1 to 6 carbon atoms;

(3) alkenyl having 2 to 6 carbon atoms;

(4) --(CH₂)_(n) M wherein n is 0 to 6 except when X is S and M is OR₅, in which case n is 1 to 6 and

M is

(a) --OR₅ ;

(b) halogen;

(c) --CF₃ ;

(d) --SR₅ ;

(e) Ar₁ ;

(f) --COOR₆ ;

(g) ##STR6## wherein R₁₂ is H, C₁ to C₆ alkyl, or Ar₁ ; (h) tetrazole; ##STR7## (m) --NR₈ R₉ ; (n) --NHSO₂ R₁₀ wherein R₁₀ is OH, C₁ to C₆ alkyl, CF₃, C₁ to C₆ -alkoxy, or Ar₁ ; ##STR8## (p) --SOR₅ ; (q) --CONR₈ R₉ ;

(r) --SO₂ NR₈ R₉ ;

(s) --SO₂ R₅ ;

(t) --NO₂ ; or

(u) --CN;

or any two of R₃, R₄, T and V may be joined to form a saturated ring having 5 or 6 ring atoms, said ring atoms comprising 0, 1 or 2 atoms selected from oxygen and sulfur, the remaining ring atoms being carbon;

each R₅ is independently H, C₁ to C₆ alkyl, benzyl, Ar₁, perfluoro-C₁ to C₄ alkyl, CH₂ --R₁₁ wherein R₁₁ is C₁ to C₅ alkyldimethylamino, hydroxy-C₂ to C₅ alkyl, CH₂ COOR₆, or CH₂ CO--R₇ ;

each R₆ is independently H or C₁ to C₆ alkyl;

each R₇ is independently C₁ to C₆ alkyl, benzyl, Ar₁, NR₈ R₉, NHAr₁, or O--C₁ to C₄ alkyl;

each R₈ and each R₉ is independently H or C₁ to C₄ alkyl, or R₈ and R₉ may be joined through the N to which they are attached to form a heterocycloalkyl ring having 5 to 8 ring atoms;

each Het is independently an aromatic heterocyclic ring having 5 or 6 ring atoms, one or more of which are selected from N, O and S;

each Ar₁ is independently 1- or 2- naphthyl, phenyl or mono- or disubstituted phenyl, wherein the substituents on the phenyl are independently selected from C₁ to C₃ alkyl, I, Br, Cl, F, COOR₆, (CH₂)_(n) --NR₈ R₉ wherein n is 0 to 2, methylenedioxy, C₁ to C₃ alkoxy, OH, CN, NO₂, CF₃, C₁ to C₄ acyl, NR₈ R₉, S-C₁ to C₆ alkyl, SO-C₁ to C₆ alkyl, and SO₂ --C₁ to C₆ alkyl; and

R₁₄ and R₁₅ are each independently H or C₁ to C₆ alkyl;

or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treatment for disease states caused by the synthesis of the Leukotriences C₄, D₄, E₄ and F₄, as well as Leukotriene B₄, in mannals especially in a human subject. This method comprises administering to said subject an effective amount of a compound of Formula I combined with an appropriate pharmaceutical carrier.

The compounds of Formula I may be used to treat or prevent mammalian (especially human) disease states such as erosive gastritis; erosive esophagitis; inflammatory bowel disease; ethanol-induced hemorrhagic erosion; hepatic ischemia; noxious agent induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CCl₄ and D-galactsoamine; ischemic rental failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced rental failure.

Finally, this invention also provides novel compounds within the Formula I that act as inhibitors of the mammalian 5-lipoxygenase enzyme system, thus preventing the biosynthesis of the Leukotrienes C₄, D₄ and E₄ and also Leukotriene B₄. 

What is claimed is:
 1. A compound of the Formula: ##STR9## wherein the substituents for compound are selected from the following groups:

    ______________________________________                                         Compound    R.sub.1  R.sub.2                                                   ______________________________________                                         162         CH.sub.3                                                                                 ##STR10##                                                163         CH.sub.3 NHPh                                                      164         CH.sub.3 NHPh-p-NO.sub.2                                           165         CH.sub.3 NHPh-p-OMe                                                166         CH.sub.3 NHPh-p-OMe                                                167         CH.sub.3 NHPh-p-NO.sub.2                                           168         CH.sub.3 NHPh-p-OMe                                                169         CH.sub.3 NHPh-p-NO.sub.2                                           170         CH.sub.3                                                                                 ##STR11##                                                171         CH.sub.3 NHPh                                                      173         CH.sub.3 NHCH.sub.2 Ph                                             174         CH.sub.3 NHPh-p-Cl                                                 175         CH.sub.3                                                                                 ##STR12##                                                176         CH.sub.3                                                                                 ##STR13##                                                177         Pr       NHPh-p-Cl                                                 178         Ph       NHPh-p-Cl                                                 181         CH.sub.3                                                                                 ##STR14##                                                182         Ph       NHPh-p-Cl                                                 183         CH.sub.3 NMePh                                                     184         CH.sub.3                                                                                 ##STR15##                                                185         CH.sub.3 NMePh                                                     186         CH.sub.3 NHPh-p-OMe                                                187         CH.sub.3                                                                                 ##STR16##                                                188         Pr       NHPh-p-Cl                                                 189         CH.sub.3 NHPh-p-Cl                                                 190         CH.sub.3 NHPh-p-Cl                                                 191         CH.sub.3 NHPh-p-OMe                                                192         CH.sub.3 NHPh-p-Cl                                                 193         Pr       NHPh-p-Cl                                                 278         CH.sub.3                                                                                 ##STR17##                                                ______________________________________                                         Compound    R.sub.3       R.sub.4                                              ______________________________________                                         162         4-OH          H                                                    163         4-OH          H                                                    164         6-OH          H                                                    165         6-OH          H                                                    166         4-OH          H                                                    167         4-OAc         H                                                    168         4-OAc         H                                                    169         4-OH          H                                                    170         4-OH          H                                                    171         4-OAc         H                                                    173         4-OAc         H                                                    174         4-OAc         H                                                    175         4-OAc         H                                                    176         4-OH          H                                                    177         6-OH          H                                                    178         6-OAc         H                                                    181         5-OH          H                                                    182         6-OH          H                                                    183         4-OAc         H                                                    184         4-OH          H                                                    185         4-OH          H                                                    186         4-OH          5-Pr                                                 187         4-OAc         H                                                    188         6-OAc         H                                                    189         4-OH          H                                                    190                                                                                         ##STR18##    5-CH.sub.2 CHCH.sub.2                                191                                                                                         ##STR19##    5-Pr                                                 192         5-OH          H                                                    193                                                                                         ##STR20##    H                                                    278         4-OH          H                                                    ______________________________________                                    


2. A method of inhibiting mammalian leukotriene biosynthesis or action which comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of claim
 1. 3. A method of claim 2 wherein the mammal is a human.
 4. A method of treating pulmonary conditions, inflammation, allergies, pain, cardiovascular conditions, or skin conditions which comprises administering to a human in need of such treatment a pharmaceutically effective amount of a compound of claim
 1. 5. A pharmaceutical composiiton useful for inhibiting the ibosynthesis of mammalian leukotrienes comprising a pharmaceuticlaly acceptable carrier and an effective amount of a compound of claim
 1. 